Click here to read the Cover Story, "For BP management in diabetes, debate continues on optimal definition, targets."
To delay progression to end-stage renal disease, all patients with diabetes should be treated with angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs) as early as possible.
Diabetic kidney disease is a frequent, serious and expensive complication of type 2 diabetes. Microalbuminuria is the first clinical sign of the disease, and we need to test for it in all patients. Once a patient has moved to microalbuminuria, we should act, even in the setting of normal blood pressure.
Blockade of the renin-angiotensin system (RAS) reduces the progression of albuminuria, may preserve kidney structure and may prevent ESRD. When someone develops macroalbuminuria, kidney function begins to decline. BP has no effect on this, according to meta-analyses, suggesting that normotensive patients also get this benefit of regression in albuminuria.
So, what do we do with patients with diabetes and microalbuminuria, or moderately elevated albuminuria and normal BP?
The American Diabetes Association guideline states that in the setting of type 2 diabetes and hypertension, defined as a BP of at least 140/90 mm Hg, and lower levels of albuminuria (30 mg/g to 299 mg/g creatinine), ACE or ARB therapy has been demonstrated to reduce the progression to more advanced albuminuria and decrease cardiovascular events. I am advocating for an early start to this intervention. To wait until a patient has overt proteinuria is too late.
Diabetes with microalbuminuria and normal BP is a small problem. Most patients with diabetes and microalbuminuria have hypertension, particularly those with type 2 diabetes. Additionally, in an observational study of more than 500 patients with type 1 diabetes and normal BP (Theilade S, et al. J Clin Hypertens. 2012;doi:10.1111/j.1751-7176.2012.00689.x), we found there was low correlation between ambulatory BP and office BP. In total, 55% to 66% of patients did not reach target BP below 130/80 mm Hg despite regular followup. In 31% to 37% of patients, office and ambulatory BP measurements disagreed in the diagnosis of hypertension. In this population, only 20% had microalbuminuria and normal BP on 24-hour readings, and 15% to 20% had masked hypertension — normal BP in the clinic, but hypertension at home (these patients were more often young, male and smokers). There are multiple studies in normotensive patients with type 2 diabetes examining progression from micro- to macroalbuminuria with ACE inhibition, all suggesting a decrease in progression of albuminuria with RAS blockade.
In Denmark we have something called the “uncle test.” What would you do if your uncle had diabetes and microalbuminuria but normal BP? “Normal” is defined by differing thresholds; however, a patient can also experience a significant increase within the normal BP range and increased albuminuria, but still not be considered hypertensive according to the guideline. Would you dare wait to treat? I hope not.
Peter Rossing, MD, is head of diabetes complications research at the Steno Diabetes Center in Gentofte, Denmark. Disclosure: Rossing reports he has served on advisory panels or received research support from Astellas Pharma, AstraZeneca, Bayer AG, Boehringer Ingelheim and Novo Nordisk, and holds shares in Novo Nordisk.
Treatment with RAS inhibitors does not prevent the development of microalbuminuria or slow the rate of formation of kidney lesions in normotensive patients with diabetes, and treatment with these drugs may increase the risk for albuminuria and CV death in certain patient populations.
We do not have good evidence that, in normotensive patients, microalbuminuria is a good surrogate for progressive diabetic kidney disease. There are several key questions when considering RAS blockade therapy in patients with diabetes, normal BP and microalbuminuria: What is “normal” BP? What are the relevant outcomes? What are the risks and benefits of treatment? What does the available evidence suggest?
To date, no clinical trials have demonstrated a beneficial effect of RAS inhibition on any relevant health outcomes in normotensive patients with diabetes who have microalbuminuria. Further, I dispute the idea that macroalbuminuria is a relevant outcome. We do not know how many of these people will ultimately progress or how long any progression may take. Relevant outcomes in a trial evaluating RAS therapies are kidney failure, CVD and CV death. Therein lies the problem, and why we have the debate, because to follow people out to these endpoints will take a long time. In clinical trials in normotensive patients with microalbuminuria, treatment with a RAS inhibitor does slow the progression of albuminuria and increase the frequency of regression; however, there is no evidence that the progression of albuminuria was associated with any reduction in the relevant outcomes, which are kidney and cardiac death.
Many patients with microalbuminuria regress spontaneously to normoalbuminuria during follow-up, and lower BP is a key predictor of that regression. Therefore, initiating lifetime treatment with RAS blockade should not be recommended in all normotensive patients with diabetes who present with microalbuminuria, as these individuals are more likely to regress even in the absence of such treatment.Early treatment with RAS inhibition may be associated with increased risk for kidney and CV events in normotensive patients with diabetes. The beneficial effects of treatment are found in those with higher BP, whereas the detrimental effects of treatment may overshadow the beneficial effects in those with lower BP.
The 2012 Kidney Disease: Improving Global Outcomes (KDIGO) clinical practice guideline states that several trials have shown the benefit of ACE inhibitors or ARBs over placebo in patients with microalbuminuria, irrespective of pretreatment BP, and ADA BP guidelines likewise suggest that clinicians may consider RAS inhibition in patients with diabetes, microalbuminuria and comorbid hypertension. That is a suggestion — not a recommendation — because we do not have evidence to say anything about it with respect to albuminuria. The ADA guideline is silent on ACE inhibitor or ARB therapy in normotensive patients with diabetes.
Some normotensive patients with diabetes and microalbuminuria, especially those with additional risk factors for diabetic kidney disease, may benefit from RAS inhibition. Others without these risk factors, however, may not benefit from such treatment. We should therefore exercise judgment in selecting which patients from this lower risk group to treat. Applying the unproven treatment to all patients with diabetes who present with microalbuminuria is not a reasonable therapeutic approach.
Robert Nelson, MD, PhD, is a senior investigator at the Phoenix Epidemiology and Clinical Research Branch of the National Institute of Diabetes and Digestive and Kidney Diseases at the NIH. Disclosure: Nelson reports no relevant financial disclosures.